Fig 1.
PRISMA flow diagram of the search study.
Fig 2.
The study flow according to the purpose (exercise training, and/or assessment of animal capacity), some methodological items that characterized the analyzed experimental protocols on pulmonary hypertension, and an example scheme for study protocols for early and late training.
CH–chronic hypoxia; MCT–monocrotaline; PA–pulmonary artery; PH–pulmonary hypertension; PAB–pulmonary artery banding; RV–right ventricle; RVSP–right ventricle systolic pressure; SU5415 –Sugen 5416; VO2max–maximal oxygen uptake.
Fig 3.
The performance of animals with pulmonary hypertension in relation to methods used for the assessment of animal exercise capacity.
The overall effect was expressed as response ratio (R), according to alterations in both hemodynamic (RVSP, mPAP) and remodeling parameters (Fulton index, PA muscularization), as well as animal exercise capacity. The increased values of response ratio (R) reveal better exercise endurance (n = 1955 animals). A statistically significant Q measure (P<0.05) indicates heterogeneity among two or more analyzed subgroups. Meta-regression plot (124 comparisons) demonstrates that worsening of PH-related parameters was significantly correlated with poorer animal exercise capacity (P = 0.0001) (A); the method chosen for the exercise tests had no influence on the resultant changes in exercise capacity (Q = 0.59; df = 2; P>0.05) (B); among a wide range of parameters that could be detected in the analyzed experiments, a similar exercise capacity (C) was observed where the following sets of parameters were considered: distance, time to exhaustion and percentage exercise capacity (Q = 2.1; df = 2; P>0.05) or values of VO2max and time to VO2max (Q = 0.19; df = 1; P>0.05).
Fig 4.
The influence of different exercise training programs on the condition of animals with PH (n = 1470 animals).
Kaplan-Meier curves demonstrate the significant differences in overall survival among particular study groups (P<0.0001) that were exposed to different exercise training-related schedules (n = 266 animals); the mortality of animals with pulmonary hypertension from sedentary groups was higher than those subjected to exercise training (P = 0.0002) (A); early training protocol did not improve survival significantly (P>0.05) as compared to these subjects with PH that were exposed to the late training program (B), animals developed PH due to injection of monocrotaline (A − B); tree-plots show that training animals were characterized with significantly better exercise endurance (Q = 4.2; df = 1; P = 0.04) and weaker PH development (Q = 4.3; df = 1; P = 0.039) as compared to their sedentary counterparts (C, E); early training programs yielded benefits in relation to exercise endurance (Q = 16.7; df = 1; P<0.0001) and PH worsening (Q = 5.85; df = 1; P = 0.016) (D, F). The overall effect was expressed as response ratio (R), according to alterations in both heamodynamic (RVSP, mPAP) and remodeling parameters (Fulton index, PA muscularization), as well as animal exercise capacity. Increased values of response ratio (R) reveal worsening of PH-related parameters and better exercise endurance (C–F). A statistically significant Q measure (P<0.05) indicates heterogeneity among two or more analyzed subgroups.
Fig 5.
The influence of some methodological items that characterize training programs on the resulting exercise endurance of animals with PH and disease development (n = 753 animals).
The overall effect was expressed as response ratio (R), according to alterations in both hemodynamic (RVSP, mPAP) and remodeling parameters (Fulton index, PA muscularization), as well as animal exercise capacity. The increased response ratio (R) values reveal worsening of PH-related parameters and better exercise endurance. A statistically significant Q measure (P<0.05) indicates heterogeneity among two or more analyzed subgroups. Tree-plot for the effect size demonstrates better results in exercise tests that were achieved by animals that were exposed to a chronic training program (treadmill subgroup) that included progressively increased speed (Q = 7.18; df = 1; P = 0.007) and incline (Q = 4.74; df = 1; P = 0.03) (A); and when the training intensity was adjusted to VO2max parameter, assessed individually (Q = 11.8; df = 1; P = 0.0006) (C); increasing intensity and slope were also related to less development of PH-related parameters in training subjects (Q = 16.1; df = 1; P<0.0001 and Q = 4.9; df = 1; P = 0.026, adequately) (B); any significant impact of individually matched training program (adjustment to VO2max) was not denoted for PH development (D).
Fig 6.
Summary of risk of bias adopted from Hooijmans et al (2014) [4].
Table 1.
Summary of potential mechanisms underlying the beneficial effects of chronic exercise training in animal models of pulmonary hypertension.
Table 2.
A summary of the major outcomes from preclinical and clinical studies on exercise training regimens for subjects with PH.